tbuckley/cabot-search huggingface dataset:
Impact of synchronous (sync) vs metachronous (meta) metastasis at the presentation on survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with androgen receptor signaling inhibitors (ARSIs).
Authors: Georges Gebrael, Nicolas Sayegh, Nishita Tripathi, Divyam Goel, James Brundage, Taylor Ryan McFarland, Hedyeh Ebrahimi, Blake Nordblad, Beverly Chigarira, Vinay Mathew Thomas, Kamal Kant Sahu, Haoran Li, Alexander Chehrazi-Raffle, Benjamin L. Maughan, Manish Kohli, Umang Swami, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2023)

5049 Background: Pts with sync metastatic castration-sensitive prostate cancer (mCSPC) appear to have worse survival outcomes and earlier time to developing castration resistance than pts with meta mCSPC (PMID: 33914595). However, the impact of the initial timing of metastasis on survival in the mCRPC setting is less clear. Herein, our objective was to assess the correlation between the sync/meta metastatic disease presentation and survival in real-world newly diagnosed mCRPC pts. Methods: In this IRB-approved study, patient-level data were collected retrospectively. Eligibility: confirmed diagnosis of mCRPC, treatment with ARSI (abiraterone or enzalutamide) as first-line (1L) therapy for mCRPC, and no prior exposure to ARSI in the mCSPC or localized states. The disease was considered sync if distant metastasis was diagnosed within 90 days of the initial prostate cancer diagnosis. Study endpoints: progression-free survival (PFS) was defined from the start of therapy for 1L mCRPC to progression (per PCWG-2) or death from any cause. Overall survival (OS) was defined from the start of therapy for 1L mCRPC to the date of death from any cause or censored at the last follow-up. A multivariate analysis using the Cox proportional hazards model was used, adjusting for potential confounders. Results: 323 pts (144 sync and 179 meta) were eligible and included in the analysis. Sync and meta pts had respectively similar baseline characteristics: median PSA (19.6 vs 20.8 ng/ml), liver metastasis (9 vs 12.3%), median alkaline phosphatase (97 vs 95 IU/L), and ECOG performance &gt; 1 (9 vs 3.9%). The difference in median PFS was not statistically significant (8.2 vs. 10.7 months, HR 1.13, 95% CI 0.85-1.49, p=0.4 for sync and meta, respectively). Median OS was significantly shorter in pts with sync compared to meta (26 vs. 38.7 months, HR 1.51, 95% CI 1.11-2.08, p=0.01). In the multivariate analysis, the initial timing of metastasis remained an independent prognostic factor. Conclusions: For the first time, we report the impact of the initial timing of metastasis on mCRPC prognosis in a real-world patient population with sync disease being associated with having a poor prognosis. Initial timing of metastasis may be worth accounting for in future mCRPC clinical trials to explore its prognostic value further. These hypothesis-generating data need external validation. [Table: see text]
Phase II study of fruquintinib as second or further-line therapy for patients with advanced biliary tract cancer.
Authors: Pengfei Zhang, Yu Yang, Hongfeng Gou, Qiu Li
Journal: Journal of Clinical Oncology (2023)

e16161 Background: Biliary tract cancer (BTC) is a rare but aggressive disease, and most patients present with unresectable or metastatic disease. Gemcitabine combined with cisplatin (GP) has been established as the standard first-line treatment in patients with unresectable BTC. Nevertheless, no standard second or further-line treatment regimen has been approved in this disease. Fruquintinib is an oral multi-kinase inhibitor targeting vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2 and VEGFR3. In this single arm phase II study, we explored the efficacy and safety of fruquintinib as a novel second or further-line therapy in advanced or metastatic BTC. Methods: BTC patients with ECOG PS 0-1 and adequate liver, kidney and bone marrow function were given fruquintinib (5 mg, PO, D1-21, Q4W) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The exploratory endpoint was the correlation of clinical outcomes with biomarkers. Results: 20 patients were enrolled in the study. 9(45.0%) were men, and the median age was 57.5(36-78) years. 18 patients were diagnosed with ICC, 1 with ECC, and 1 with GBC. 6 (30%) patients were refractory to second-line treatment, and 5 (25%) patients were refractory to third-line treatment. 18 patients were assessable for response. The median PFS was 4.6 months (95%CI: 2.1-7.1 months). ORR was 5.6%, and DCR was 66.7%. The incidence of treatment-related grade 1-2 adverse events (TRAEs) was 83.3%, and the most common grade 1-2 AEs were hand-foot syndrome (66.6%), fatigue (61.1%), stomatitis (44.4%), and hypertension (38.9%). Conclusions: Fruquintinib showed promising efficacy and acceptable toxicity as second or further-line therapy in advanced or metastatic BTC. Clinical trial information: NCT04156958 .
A phase I/II trial of NOX66 in combination with nivolumab in patients (pts) with advanced cancer.
Authors: Paul L. de Souza, Bo Gao, Gavin M. Marx, Adam James Cooper, Kate Jessica Wilkinson, Luke McPherson, Amy Erskine, Sheri Nixdorf, Leigh Putterill, Timothy Mann, Mila Sajinovic, Shadma Fatima, Kieran Scott
Journal: Journal of Clinical Oncology (2023)

e14591 Background: NOX66 (idronoxil) targets ENOX2 and suppresses STING-mediated inflammatory pathways, reducing IFN and NFκB driven cytokine production by cancer cells. Adding NOX66 to nivolumab may help overcome resistance mechanisms to checkpoint inhibitors and improve responses in patients. Methods: IONIC-1, is an open label Phase I/II trial evaluating safety and preliminary efficacy of NOX66 (suppositories daily x 1 week, then 1 week rest) combined with nivolumab (240mg IV every 2 weeks). Three dose cohorts of NOX66 are planned (1200mg daily, 1800mg daily, 2400mg daily). Objectives include safety, tolerability, and clinical and radiological responses. Two groups are being studied: 1) Pts who have prior progression on a checkpoint inhibitor; 2) Pts naïve to checkpoint inhibitors. Results: 11 pts have been treated to date; 3 in Group 1, and 8 in Group 2. All pts have received at least 2 cycles of the combination treatment; 2 pts completed 8 cycles, and 2 pts remain on study. Tumour types include lung, prostate, gastric, pancreatic, nasopharyngeal and metastatic squamous carcinoma. Early signals of tumour response based on RECIST 1.1 criteria include stable disease in 2 pts (SD at 8 weeks and at 16 weeks); partial response (PR) in 1 patient at 16 weeks; complete response (CR) in 2 pts, both with ongoing CR at 24 weeks. Five pts had disease progression, and 1 pt was withdrawn due to suspected immune mediated myositis and hepatitis resulting from nivolumab and was not evaluable. The most common AE was local perineal irritation, readily managed with topical corticosteroid cream. Two pts developed an erythematous rash over the trunk and limbs after 2 cycles, suspected to be related to the combination treatment. Using a 32 multiplexed immune cytokine assay to evaluate the single-cell functional states of CD4+ and CD8+ T cells in patients’ peripheral blood mononuclear cells (PBMCs) at pre-treatment and at Cycle 3 Day 1, we found a significant increase in polyfunctionality in both effector CD4+ and CD8+ve T cells compared to baseline in responder patients. Conclusions: Preliminary analysis shows promising tumour responses from the combination therapy which appears to be well-tolerated, with no safety signals evident to date. Clinical trial information: ACTRN12621001537842 .
Alteration of gut microbiota composition in patients with cholangiocarcinoma with non-responsiveness to first-line chemotherapy: A pilot study.
Authors: Thanika Ketpueak, Sirawit Sriwichaiin, Kanokphong Suparan, Sasiwan Kerdphoo, Chaiyut Charoentum, Thatthan Suksombooncharoen, Busyamas Chewaskulyong, Nipon Chattipakorn, Siriporn Chattipakorn
Journal: Journal of Clinical Oncology (2023)

4104 Background: Gut microbiota established crucial roles in host metabolism and several diseases, particularly cancers. Distinct bacterial profiles from intestine are found to be a potential factor in carcinogenesis, while some of those are associated with detrimental treatment to the responsiveness in various types of cancer. Association of gut microbiota and treatment outcome has been thoroughly investigated in intrahepatic cholangiocarcinoma (ICCA). The present study aimed to compare gut microbiota profiles between chemotherapy responder and non-responder in ICCA patients. Methods: Unresectable or metastatic ICCA patients were recruited in the study. The criteria of all patients were naïve to chemotherapy. All patients received first line combination of cisplatin 25 mg/m 2 and gemcitabine 1000 mg/m 2 at day1 and day 8 in every 21-day cycle and were given up to 8 cycles. The primary endpoint was to evaluate the association between gut microbiota and the objective response rate. Bacterial genomic DNA samples were extracted from the stool using a commercial genomic DNA isolation kit (Qiagen, Hilden, Germany) and then underwent next-generation sequencing. Data analyses were conducted by using QIIME2 and Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC). Results: Seventeen ICCA patients were recruited. The objective response rate was 23.5% comparable to historical study. Chemotherapy responder group was defined as partial response patients (N = 4) and chemotherapy non-responder group included stable of disease and progressive disease (N = 13). Baseline characteristics were similar including age, sex, ECOG performance status, numbers of metastatic organ and CA 19-9 in two groups. Median Age were 63 years old (60-70) and 61 (45-73), respectively. Alpha-diversity and beta-diversity were not different between two groups. In chemotherapy non-responder group, some taxa were dominantly observed including Ruminococcaceae, Oribacterium, Oxalobacter, Peptostreptococcus, Aggregabacter, which had been previously reported increasing in ICCA patients. Interestingly, Ruminococcaceae, which was previously documented to be correlated with vascular invasion, was significantly increased abundance in non-responder group. Moreover, the median progression-free survival (PFS) was improved in chemotherapy responder group compared to non-responder group 11.8 and 6.6 month, respectively. Large sample sizes study to confirm this study result should be developed. Conclusions: Distinct bacteria from gut microbiota such as Ruminococcaceae has inversely associated with chemotherapy response in ICCA patients receiving first line cisplatin and gemcitabine combination, suggesting the possibility of the poorer PFS.
Temporal patterns of immune-mediated adverse events (imAEs) with tremelimumab (T) plus durvalumab (D) in the phase 3 HIMALAYA study in unresectable hepatocellular carcinoma (uHCC).
Authors: George Lau, Bruno Sangro, Oxana V. Crysler, Wattana Sukeepaisarnjaroen, Oleg Lipatov, Manabu Morimoto, Isabelle Archambeaud, Valentina Burgio, Le Thi Tuyet Phuong, Yee Chao, Jean-Marie Peron, Marie-Luise Berres, Yoo-Joung Ko, Carrie L. McCoy, Charu Gupta, Mallory Makowsky, Alejandra Negro, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2023)

4073 Background: In the Phase 3 HIMALAYA study (NCT03298451) in uHCC, STRIDE (Single T Regular Interval D) significantly improved overall survival versus sorafenib (S) and had manageable safety (Abou-Alfa et al. NEJM Evid 2022). STRIDE is approved for uHCC in the United States and Japan and is recommended for approval by the European Medicines Agency. In this exploratory post hoc analysis, we assessed temporal patterns of imAEs for the STRIDE regimen in HIMALAYA. Methods: Safety was assessed in participants (pts) who received ≥1 dose of STRIDE (T 300 mg [one dose] plus D 1500 mg once every 4 weeks) or S (400 mg twice daily). Treatment causality was investigator-assessed. imAEs were defined as AEs of special interest associated with drug exposure and consistent with an immune-mediated mechanism of action for which no alternate etiology was clear. Safety was summarized descriptively overall and at specific time points after the start of treatment. Results: In total, 388 (STRIDE) and 374 (S) pts were included in the safety analysis. Median (range) duration of exposure was 5.5 (0.4–41.9) months for STRIDE (D exposure in STRIDE) and 4.1 (0.1–38.6) months for S. Any grade treatment-related AEs (TRAEs) and Grade 3 or 4 TRAEs were less frequent for STRIDE (75.8% and 25.8%, respectively) versus S (84.8% and 36.9%, respectively). Any grade imAEs and max Grade 3 or 4 imAEs occurred in 35.8% and 12.6% of pts, respectively for STRIDE. Any grade imAEs and max Grade 3 or 4 imAEs with STRIDE occurred at all time points assessed and were most likely to occur within the first three months after treatment. For STRIDE, any grade imAEs of gastrointestinal disorders and skin and subcutaneous tissue disorders were most common within the first month after treatment (3.9% and 3.1%, respectively), whereas any grade imAEs of endocrine disorders were most common between &gt;1 and ≤2 months (6.7%). Conclusions: In HIMALAYA, AEs with STRIDE were manageable and generally low grade. Any grade TRAEs and Grade 3 or 4 TRAEs were less frequent for STRIDE versus S. Although imAEs with STRIDE could occur at any time, most were observed within the first three months after treatment. These findings continue to support STRIDE for the treatment of uHCC. Clinical trial information: NCT03298451 . [Table: see text]
Deep learning-based histomorphological pattern profiles for effective risk stratification in prostate cancer.
Authors: JaeHeon Lee, Tae-Yeong Kwak, Joonyoung Cho, Sun Woo Kim, Hyeyoon Chang
Journal: Journal of Clinical Oncology (2023)

e17107 Background: Prostate cancer affects millions of men globally and biochemical recurrence (BCR) is an important indicator of its progression. With the increasing use of computational techniques, there has been a growing interest in utilizing whole slide images (WSIs) of H&amp;E stained prostate tissue to evaluate the patients’ clinical risks. Our study aimed to develop a novel method for predicting BCR by performing clustering on features extracted from deep learning models, thereby capturing morphological characteristics. Methods: The WSIs and clinical information were collected from The Cancer Genome Atlas (TCGA, from 2000 to 2013) dataset, for 321 patients (43 patients with BCR) who were not treated with any adjuvant therapies, with 2.5 years of median follow-up time. 356 collected WSIs were split into 1024 x 1024 patches at 5x magnification for the deep learning-based analysis. We used an ImageNet-pretrained deep learning-based clustering model (SwAV) to extract features from each patch and applied additional K-means clustering to assign the patches into one of 16 clusters. We tested both the cosine similarity and Euclidean distance as the clustering measure. After excluding the dissimilar patches under specific thresholds, the proportion of each cluster was calculated per slide to describe the distribution of morphological patterns as a 16-dimensional vector. To evaluate the predictability, we trained Cox models with the proportion vectors and assessed their performance via the concordance index (c-index). We repeated a stratified 5-fold cross-validation process 100 times to achieve robustness. As a reference, we conducted the same experiment with a BCR prediction nomogram published by MSKCC. Moreover, with the median proportion of each cluster, we separated two patient groups, drawed Kaplan-Meier curves, performed the log-rank test for significance, and we obtained the hazard ratio (HR) of each cluster from the trained Cox model of each fold. Results: We explored several thresholds to find ones yielding the best performance. When using the similarity, the best c-index was 0.704 with the threshold value of 0.25. With the distance value of 0.60, the c-index was 0.701. When using the MSKCC nomogram that incorporates clinical features, the average c-index was 0.717. The table contains the results of statistical analysis for selected clusterings that were significant in the log-rank test. Particularly in cluster B, the patches showed high-risk patterns including perineural invasion, high grade cancer, and necrosis in agreement with the high HR. Conclusions: Our results suggest that the histomorphological pattern profiles depicted by the deep learning model have the potential for effective risk stratification in prostate cancer. [Table: see text]
Serum soluble MAdCAM-1: A new biomarker for cancer immunotherapy.
Authors: Carolina Alves Costa Silva, Marine Fidelle, Roxanne Birebent, Cécile Dalban, Silvia Zoppi, Anna Reni, Conrad Rauber, Imran Lahmar, Anne-Laure Mallard de La Varende, Nathalie Rioux-Leclercq, Catherine Sautès-Fridman, Maxime Meylan, Yann-Alexandre Vano, Benoit Beusenlick, Salem Chouaib, Florence Tantot, Bernard Escudier, Laurence Zitvogel, Lisa Derosa, Laurence Albiges
Journal: Journal of Clinical Oncology (2023)

4548 Background: Antibiotics (ATB) deviate the gut taxonomic microbiota composition and have a deleterious impact on survival in ICI-treated pts. ATB downregulate the ileal mucosal addressin cell adhesion molecule-1 (MAdCAM-1), leading to the recirculation of immunosuppressive enterotropic T cells into the tumor and ICI resistance. Here, we aimed to assess the prognostic impact of MAdCAM-1 in ICI-treated mRCC pts. Methods: The GETUG-AFU 26 NIVOREN phase II trial (NCT 0301335) is a multicentric study that assessed the activity and safety of Nivolumab in pts with clear cell mRCC after anti-angiogenic therapy. We measured serum soluble MAdCAM-1 (sMAdCAM-1) levels (correlating ileal MAdCAM-1 transcripts) using Human Luminex Discovery Assay in the available plasma. Progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR) were assessed using sMAdCAM-1 median as a cut off value (high if &gt;median and low if &lt;median). Multivariate Cox analysis adjusted for established risk factors: ATB, gender, age, international Metastatic RCC Database Consortium (IMDC) score, number of previous lines, hypoalbuminemia, and brain, bone and liver metastasis. Two independent cohorts of metastatic lung and bladder cancer patients validated the data. Results: Overall, 212 pts were included. Median age was 64 years (22-87), and pts were mostly male (82%). ATB users had lower levels of sMadCAM-1. Low sMadCAM-1 pts had diminished OS compared to high sMadCAM-1 pts [HR 2.97 (95%CI 1.99-4.44), p&lt;.0001]: 13.3 (95%CI 9.8-14.9; 72/106) versus 25.3 (95%CI 24.1-NR; 36/106) months. Also, low sMadCAM-1 pts had diminished PFS [HR 1.92 (1.43-2.57), p&lt;.0001]: 2.6 (95%CI 2.4-2.8; 99/106) versus 5.2 (95%CI 4.6-5.7; 86/106) months. Interestingly, sMAdCAM-1 was independently associated with OS [HR 2.40 (1.52-3.80), p=0.0002] and PFS [HR 1.55 (1.13-2.13), p=0.0071] in multivariate analysis. Low sMadCAM-1 pts had lower CBR (37% versus 63%, p=0.0004). Serum sMAdCAM-1 also predicted OS in 381 ICI-treated patients with lung and bladder cancer. Conclusions: Low sMAdCAM-1 is associated with ATB intake, ATB-independent gut dysbiosis and worse outcomes, in ICI-treated pts with metastatic lung, bladder and RCC cancer. ELISA determination of sMAdCAM-1 might guide the selection of patients amenable to microbiota-centered interventions, such as Akkermansia sp., and fecal microbiota transplantation. Clinical trial information: NCT0301335 .
Prognostic and predictive significance of pre- and post-operative plasma tumor markers in patients with appendiceal adenocarcinoma undergoing cytoreductive surgery: Insights from a single-center study.
Authors: Abdelrahman M.G. Yousef, Mahmoud M.G. Yousef, Mohammad A. A. Zeineddine, Ichiaki Ito, Saikat Chowdhury, Yue Gu, Mark Knafl, Jeff Jin, Paul Edelkamp, Abhineet Uppal, Neal Bhutiani, Kristin Alfaro-Munoz, Neus Neus Bota-Rabassedas, Beth A Helmink, Michael White, Melissa Taggart, Kanwal Pratap Singh Raghav, Michael J. Overman, Keith F. Fournier, John Paul Y.C. Shen
Journal: Journal of Clinical Oncology (2023)

3539 Background: Appendiceal adenocarcinomas (AA) are both rare and heterogeneous diseases. Cytoreductive (CRS) surgery followed by heated intraperitoneal chemotherapy (HIPEC) remains the best treatment for AA patients with peritoneal metastasis. This study seeks to investigate the clinical utility of pre- and post-operative plasma tumor markers (TM, CEA, CA19-9, CA-125) by association with survival outcomes. Methods: Under an approved IRB protocol the Palantir Foundry software system was used to query MD Anderson internal database to identify patients with AA who underwent CRS between 2016 to 2022. Elevation of TM was defined as above the laboratory upper limit of normal (CEA &gt; 3 ng/mL, CA 19-9 &gt; 37 U/mL, and CA-125 &gt; 37 U/mL). Relationship between normal and elevated serum TM and progression-free survival (PFS) and overall survival (OS) was evaluated using univariate and multivariate Cox-proportional hazards regression analysis, considering multiple clinicopathologic variables. Results: 296 patients were identified; preoperative CEA, CA19-9 and CA125 was elevated in 60%, 29% and 28% of patients, respectively. Preoperative elevation of any TM was associated with higher PCI score (22 vs. 15, p&lt; 0.0001). Moreover, elevated preoperative TM was associated with incompleteness of cytoreduction (OR = 6.5, p&lt; 0.0001). Compared to preoperative measurements, all TM levels dropped after surgery (Mean score 31 vs 11 for CEA, 136 vs 32 for CA19-9 and 36 vs 17 for CA125). Preoperative elevation of any TM (HR = 1.5, p= 0.0288) and post-op elevation of any TM were with poor PFS on univariate analysis, however only post-op elevated TM levels (HR = 2.3, p= 0.0001) were associated with poor PFS on multivariate analysis. Interestingly, elevated TM was not associated with OS. Post-op TM levels were analyzed to evaluate the positive and negative predictive value in prediction of relapse in 6 months from surgery, PPV was 45% and NPV was 84%. Conclusions: Preoperative elevation of TM can identify patients at higher risk for incomplete cytoreduction and relapse after surgery. Postoperative elevation of TM is a risk factor for relapse. [Table: see text]